Introduction of Mutant GNAQ into Endothelial Cells Induces a Vascular Malformation Phenotype with Therapeutic Response to Imatinib

GNAQ is mutated in vascular and melanocytic lesions, including vascular malformations and nevi. No in vivo model of GNAQ activation in endothelial cells has previously been described. We introduce mutant GNAQ into a murine endothelial cell line, MS1. The resultant transduced cells exhibit a novel phenotype in vivo, with extensive vasoformative endothelial cells forming aberrant lumens similar to those seen in vascular malformations. ATAC-seq analysis reveals activation of c-Kit in the novel vascular malformations. We demonstrate that c-Kit is expressed in authentic human Sturge–Weber vascular malformations, indicating a novel druggable target for Sturge–Weber syndrome. Since c-Kit is targeted by the FDA-approved drug imatinib, we tested the ability of imatinib on the phenotype of the vascular malformations in vivo. Imatinib treated vascular malformations are significantly smaller and have decreased supporting stromal cells surrounding the lumen. Imatinib may be useful in the treatment of human vascular malformations that express c-Kit, including Sturge–Weber syndrome.

A Right Thalamo-Choroidal Arterio-Venous Malformation and Associated Vein of Galen Aneurysm in a Female Adult

Vein of Galen aneurysm (VGAM) is a rare vascular malformation accounting for less than 1% of all intracranial abnormalities. In this case report, we performed computed tomography (CT) and magnetic resonance imaging (MRI) examinations for a 26-year-old female patient who presented with a severe headache. On these images, a right thalamo-choroidal arterio-venous malformation (AVM) with secondary aneurysmal dilatation of the vein of Galen was suspected, and a CT angiography was performed for further evaluation, which confirmed the diagnosis. The patient refused digital subtraction angiography (DSA) and probable endovascular treatment. Although it is rarely seen in the adult population, CT and MRI have a tremendous impact on the diagnosis of these patients. We should also emphasize the role of CT angiography in the diagnosis and further evaluation of these vascular malformations. Endovascular therapy is regarded as an effective and safe technique in the treatment of these patients.

Initial Experience Using the Transradial Approach for Endovascular Treatment of Vascular Pathologies: Safety and Feasibility

Background Endovascular treatment of vascular pathologies through the transradial approach has been increasingly used and has demonstrated a low rate of complications. Objective To report our initial experience in the endovascular treatment of cerebrovascular diseases with the transradial approach and to determine its safety and feasibility. Methods Consecutive patients who underwent the transradial approach for endovascular treatment of aneurysms and vascular malformations were reviewed at a single institution. Technical success, fluoroscopy time, and access-related complications were analyzed. Results Eight patients underwent endovascular treatment with the transradial approach. One arteriovenous fistula, one superficial temporal artery aneurysm, three arteriovenous malformations, and four aneurysms were treated successfully. The radial artery was successfully approached and a 6-F sheath was used in all the cases. Navigation of guiding catheters (5 and 6 F) was done without complications. The most commonly approached artery was the right internal carotid artery, followed by the right vertebral artery. Postoperative vasospasm was identified in three patients. Mean fluoroscopy time was 34.7 minutes. Conversion to transfemoral approach was not required. No postoperative complications were reported. Conclusions In our initial experience, the transradial approach is a safe and feasible alternative for the endovascular treatment of cerebrovascular pathologies.

Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction

Increased soluble endoglin (sENG) were observed in human brain arteriovenous malformations (bAVMs), and overexpression of sENG with vascular endothelial growth factor (VEGF)-A induced dysplastic vessel formation in mouse brain. However, the underlying mechanism of sENG-induced vascular malformations is not clear. While evidence suggests the role of sENG as a pro-inflammatory modulator, increased microglial accumulation and inflammations were observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that sENG with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, there were increased microglial activation around dysplastic vessels with expression of NLRP3, inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1β), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs while it decreased IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to release angiogenic/inflammatory responses which may be involved in EC dysfunction. Our study suggests the contribution of microglia in the pathology of sENG-associated vascular malformations.

Complex vascular anomalies and tissue overgrowth of limbs associated with increased skin temperature and peripheral venous dilatation: parks weber syndrome or PROS?

PIK3CA-related overgrowth spectrum (PROS) is a series of congenital, sporadic disorders that are associated with segmental overgrowth phenotypes and postzygotic, somatic gene mutations in the PIK3CA-ATK-mTOR pathway. The variability and overlapping phenotypes between PROS and other complex vascular malformations make the differential diagnosis confusing and challenging. PROS should be considered for the differential diagnosis with other complex vascular malformations and syndromes with a tissue overgrowth phenotype, such as Parkes-Weber syndrome (PWS).Herein, we diagnosed one unique clinically challenging case manifested as capillary malformation (CM), limb overgrowth, as well as increased skin temperature and peripheral venous dilatation of lower limb that indicated a potential fast-flow lesion. The patient was initially diagnosed with PWS. Contrary to the previous diagnosis, based on further MR imaging and digital subtraction angiography (DSA), which ruled out the existence of AVMs and AVFs, and molecular analysis with targeted next-generation sequencing (NGS) revealing a somatic PIK3CA mutation, we ultimately diagnosed that the patient had a unique form of PROS simulating PWS phenotypes. We suggest that it is important to propose the differential diagnosis of PWS and PROS, two diseases that share a common overgrowth phenotype. We recommended radiological diagnosis such as MRI, CT and DSA as well as further molecular diagnosis to provide more information for the assessment of vascular lesions and to further guide clinical treatment strategies.

Endovascular Management of Hemorrhagic Stroke

Significant advances in endovascular neurosurgery tools, devices, and techniques are changing the approach to the management of acute hemorrhagic stroke. The endovascular treatment of intracranial aneurysms emerged in the early 1990s with Guglielmi detachable coils, and since then, it gained rapid popularity that surpassed open surgery. Stent-assisted coiling and balloon remodeling techniques have made the treatment of wide-necked aneurysms more durable. With the introduction of flow diverters and flow disrupters, many aneurysms with complex geometrics can now be reliably managed. Arteriovenous malformations and fistulae can also benefit from endovascular therapy by embolization using n-butyl cyanoacrylate (NBCA), Onyx, polyvinyl alcohol (PVA), and coils. In this article, we describe the role of endovascular treatment for the most common causes of intracerebral and subarachnoid hemorrhages, particularly ruptured aneurysms and vascular malformations.